title: Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus.
abstract: Systemic lupus erythematosus (SLE) is a severe and incurable autoimmune disease characterized by chronic activation of plasmacytoid dendritic cells (pDCs) and production of autoantibodies against nuclear self-antigens by hyperreactive B cells. Neutrophils are also implicated in disease pathogenesis; however, the mechanisms involved are unknown. Here, we identified in the sera of SLE patients immunogenic complexes composed of neutrophil-derived antimicrobial peptides and self-DNA. These complexes were produced by activated neutrophils in the form of web-like structures known as neutrophil extracellular traps (NETs) and efficiently triggered innate pDC activation via Toll-like receptor 9 (TLR9). SLE patients were found to develop autoantibodies to both the self-DNA and antimicrobial peptides in NETs, indicating that these complexes could also serve as autoantigens to trigger B cell activation. Circulating neutrophils from SLE patients released more NETs than those from healthy donors; this was further stimulated by the antimicrobial autoantibodies, suggesting a mechanism for the chronic release of immunogenic complexes in SLE. Our data establish a link between neutrophils, pDC activation, and autoimmunity in SLE, providing new potential targets for the treatment of this devastating disease.
authors.affiliation: Department of Immunology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Lande
authors.forename: Dipyaman
authors.initials: D
authors.lastname: Ganguly
authors.forename: Valeria
authors.initials: V
authors.lastname: Facchinetti
authors.forename: Loredana
authors.initials: L
authors.lastname: Frasca
authors.forename: Curdin
authors.initials: C
authors.lastname: Conrad
authors.forename: Josh
authors.initials: J
authors.lastname: Gregorio
authors.forename: Stephan
authors.initials: S
authors.lastname: Meller
authors.forename: Georgios
authors.initials: G
authors.lastname: Chamilos
authors.forename: Rosalie
authors.initials: R
authors.lastname: Sebasigari
authors.forename: Valeria
authors.initials: V
authors.lastname: Riccieri
authors.forename: Roland
authors.initials: R
authors.lastname: Bassett
authors.forename: Hideki
authors.initials: H
authors.lastname: Amuro
authors.forename: Shirou
authors.initials: S
authors.lastname: Fukuhara
authors.forename: Tomoki
authors.initials: T
authors.lastname: Ito
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
authors.forename: Michel
authors.initials: M
authors.lastname: Gilliet
mesh_terms: D000974:Antibodies, Antinuclear / Q000097:blood; D000936:Antigen-Antibody Complex / Q000097:blood; D023181:Antimicrobial Cationic Peptides; D001324:Autoantigens / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D054804:Cathelicidins / Q000276:immunology; D004247:DNA / Q000097:blood / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation; D009504:Neutrophils / Q000276:immunology*; D010455:Peptides / Q000097:blood / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000378:metabolism
chemical_list: D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D023181:Antimicrobial Cationic Peptides; D001324:Autoantigens; D054804:Cathelicidins; D010455:Peptides; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D004247:DNA